1. Field of the Invention
This invention relates to the field of treating patients having congestive heart failure with growth hormone and insulin-like growth factor I in the presence or absence of an angiotensin-converting enzyme (ACE) inhibitor.
2. Description of Related Art
In vitro studies have shown that chronic hypersecretion of growth hormone (GH) by implantation of a GH-secreting tumor in rats leads to increased isometric force without affecting the unloaded shortening velocity of isolated cardiac papillary muscles, despite a marked shift of the isomyosin pattern toward the low ATPase activity V3 isoform. These results suggest that GH may induce a pattern of myocardial contraction that allow the cardiac muscle to function more economically. Timsit, J. et al., J. Clin. Invest. 86:507-515 (1990); Timsit, J. et al., Acta. Paediatr. Suppl. 383:32-34 (1992). The increase in the contractile performance was shown to be due to specific alterations in the properties of the contractile apparatus, including an increase in both maximal tension and myofibrillar sensitivity to calcium. Mayoux, E. et al., Circulation Research 72(1):57-64 (1993). However, hemodynamic studies in vivo in anesthetized rats subjected to chronic GH hypersecretion have yielded conflicting results, with either increased or decreased indices of cardiac performance. Penney, D. G. et al., Cardiovascular Research 19:270-277 (1985); Rubin, S. A. et al., J. Mol. Cell Cardiol. 22:429-438 (1990). The inconsistency between these two in vivo studies is probably related to effects of anesthesia on hemodynamics. Further, a clinical study has demonstrated that GH administration increases myocardial contractility and cardiac output in normal man. Thuesen, L. et al., Dan. Med. Bull. 35(2):193-196 (1988). Treatment with GH causes a significant increase in cardiac performance and improvement of exercise capacity in GH deficient adult humans. Jorgensen, J. et al., The Lancet i: 1221-1225 (1989); Cuneo, R. et al., J. Appl. Physiol. 70:695-700 (1991); Christiansen, J. S. et al., Acta. Paediatr. Suppl. 383:40-42 (1992); Amato, G. et al., J. Clin. Endocrinol. Metab. 77:1671-1676 (1994); Caidahl, K. et al., Clin. Endocrinol. 40:393-400 (1994). Previous studies have shown that GH treatment for two weeks improved cardiac function by increasing ventricular contractility and by decreasing peripheral vascular resistance in conscious rats with congestive heart failure. Yang, R. et al., Clinical Research 42(2):325A (1994).
Insulin-like growth factor (IGF-I) has been shown to promote actin synthesis in myocytes in culture (Florini, J. R., Muscle and Nerve 10:577-598 [1987]) and to increase the contractility of neonatal rat cardiocytes in vitro. Vetter, U. et al., Basic Res. Cardiol. 83:647-654 (1988). Acute intravenous administration (infusion or bolus injection) of IGF-I produces increases in stroke volume and cardiac output in normal lambs. Gluckman et al., PCT WO 92/11865 (1992). In rats with doxorubicin induced cardiomyopathy, chronic treatment with IGF-I for 3 weeks increases cardiac output and stroke volume. Ambler, G. R. et al., Cardiovascular Research 27:1368-1373 (1993).
The effect of GH on circulating levels of glucose is opposite that of IGF-I. GH administration can cause glucose intolerance or increase blood sugar levels, producing hyperglycemia in humans. Sherwin. R. S. et al., Diabetologia 24:155-156 (1983); Metcalfe, P. et al., Diabetologia 20:123-128 (1981). In contrast, subcutaneous or intravenous administration of IGF-I can lower blood glucose, inducing hypoglycemia in humans. Guler, H. P. et al., N. Engl. J. Med. 317:137-140 (1987); Takano, K. et al., Endocrinol. Japan. 37(2):309-317 (1990); Froesch, E. R. et al., Trends Endocrinol. Metab. 1:254-260 (1990). Further, a clinical study has demonstrated that the combination of GH and IGF-I treatment is substantially more anabolic than either GH or IGF-I alone. The combination also prevents the hyperglycemia caused by GH alone and attenuates the hypoglycemia induced by IGF-I alone in normal subjects. Kupfer, S. R. et al., J. Clin. Invest. 91:391-396 (1993); Clemmons, D. R. et al., J. Clin. Endocrinol. Metab. 75:234-238 (1992).
Heart failure affects approximately three million Americans. New cases of heart failure number about 400,000 each year. Congestive heart failure is a syndrome characterized by left ventricular dysfunction, reduced exercise tolerance, impaired quality of life, and markedly shortened life expectancy. Decreased contractility of the left ventricle leads to reduced cardiac output with consequent systemic arterial and venous vasoconstriction. This vasoconstriction, which promotes the vicious cycle of further reductions of stroke volume followed by an increased elevation of vascular resistance, appears to be mediated, in part, by the renin-angiotensis system. The key component of this system, the potent vasoconstrictor, angiotensin II, also has the effect of stimulating aldosterone secretion, possibly enhancing sympathetic drive and increasing vasopressin secretion. Cohn, J. N. et al., N. England J. Med. 325(5):303-310 (1991); Captopril Multicenter Research Group, J.A.C.C. 2(4):755-763 (1983). Angiotensin-converting enzyme (ACE) inhibitors, such as captopril, have become standard therapy for patients with congestive heart failure. These drugs improve hemodynamic profile and exercise tolerance and reduce the incidence of morbidity and mortality in patients with congestive heart failure. Kramer, B. L. et al., Circulation 67(4):807-816 (1983); Captopril Multicenter Research Group, J.A.C.C. 2(4):755-763 (1983); The CONSENSUS Trial Study Group, N. Engl. J. Med. 316(23):1429-1435 (1987); The SOLVD Investigators, N. Engl. J. Med. 325(5):293-302 (1991). However, despite proven efficacy, response to ACE inhibitors has been limited. Improvement of functional capacity and exercise time is only small and mortality, although reduced, continues to be high. The CONSENSUS Trial Study Group, N. Engl. J. Med. 316(23):1429-1453 (1987); The SOLVD Investigators, N. Engl. J. Med. 325(5):293-302 (1991); Cohn, J. N. et al., N. Engl. J. Med. 325(5):303-310 (1991); The Captopril-Digoxin Multicenter Research Group, JAMA 259(4):539-544 (1988). GH and IGF-I have each been shown separately to improve cardiac performance. However, until now the effects of the combination of GH and IGF-I in heart failure have not been evaluated, either in the presence or absence of captopril.
Accordingly, it is an object of this invention to provide a method of treatment for patients with congestive heart failure, the method comprising administering to the patient GH and IGF-I in addition to an ACE inhibitor. It is well known, that captopril alone, for example, improves cardiac function by decreasing peripheral vascular resistance. Captopril together with GH and IGF-I cause greater improvement of cardiac performance than does captopril alone.
It is another object of this invention to provide a method of treatment for patients with congestive heart failure, the method comprising treating the patients with an effective amount of a combination of GH and IGF-I in the absence of an ACE inhibitor. The administration of GH and IGF-I in combination produces improvement of cardiac performance by increased ventricular contractility and decreased peripheral vascular resistance.
Improvement in cardiac performance for patients with congestive heart failure may be achieved in patients being treated with ACE inhibitors by adding to the treatment regimen a combination of GH and IGF-I. Improvement in cardiac performance in these patients may also be achieved by administration of GH/IGF-I and an ACE inhibitor from the outset of treatment.